PROJECT 1 COGNITIVE IMPAIRMENT AND DECLINE IN PARKINSON DISEASE One of the most frequent and disabling developments in the mid- and later stages of Parkinson disease (PD) is the development of cognitive impairment, leading to dementia. The specific mechanism(s) leading to dementia in PD are at present unknown. However, postmortem pathological examinations of PD brains reveal degenerative changes in the basal forebrain and cerebral cortex that may account for dementia in advanced disease. In addition, there are variable proportions of demented PD patients in whom some changes typical of Alzheimer disease (AD) are seen also. It will be important to better understand the mechanism(s) leading to dementia in PD as improved treatments for the motor symptoms and the progressive losses of brainstem dopaminergic neurons are developed. If these treatments do not address the processes leading to more widespread pathology in PD, overall morbidity and mortality in PD may not be improved. In the present project, we will recruit and characterize a cohort of PD patients with moderate motor PD severity, and who are at increased risk for the development of dementia. We will perform behavioral and cognitive testing at baseline, together with PET imaging of dopaminergic degeneration and basal forebrain cholinergic degeneration with the radiotracers [11C]DTBZ to map vesicular monoamine transporter binding sites and [11C]PMP to measure acetylcholinesterase hydrolysis rates, respectively. We will additionally perform imaging with [11C]PIB to detect pathological cerebrocortical deposition of fibrillary A3 amyloid protein (the "senile" plaques of AD). Patients will be followed prospectively over 2 years with repeat neuropsychometric measures to determine interval cognitive decline. We will assess the relationships between the PET neurodegenerative measures and the loss of cognitive function over time to address the neurochemical mechanism(s) that may be present. In addition, we will conduct a multivariate analysis of the PET measures to assess the possible presence of a global process linking the dopaminergic and cholinergic degenerations and the development of Af3 amyloid deposition.